Obesity is a chronic metabolic disorder that has reached epidemic proportions in many areas of the world and is the major risk factor for serious co-morbidities such as type 2 diabetes mellitus, cardiovascular disease, dyslipidaemia and certain types of cancer (World Health Organ Tech Rep Ser. 2000; 894:i-xii, 1-253).
It has long been recognized that low calorie dietary interventions can be very efficient in reducing weight and that this weight loss is generally accompanied by an improvement for the risk of obesity related co-morbidities, in particular type 2 diabetes mellitus. Empirical data suggests that a weight loss of at least 10% of the initial weight results in a considerable decrease in risk for obesity related co-morbidities (World Health Organ Tech Rep Ser. 2000; 894:i-xii, 1-253). However, the capacity to lose weight shows large inter-subject variability.
It has been shown that a percentage of the population do not successfully lose weight on a low calorie diet (Ghosh, S. et al., Obesity (Silver Spring), (2011) 19(2):457-463). This leads to an unrealistic expectation of weight loss, which in turn causes non-compliance, drop-outs and generally unsuccessful dietary intervention.
Some studies also demonstrate that there are methods in the art for monitoring weight loss which include monitoring levels of particular biomarkers in plasma (e.g. Lijnen et al., Thromb Res. 2012 January, 129(1): 74-9; Cugno et al., Intern Emerg Med. 2012 June, 7(3): 237-42; and Bladbjerg et al., Br J Nutr. 2010 December, 104(12): 1824-30). However, these methods do not provide a prediction or indication of the degree of weight loss attainable by a particular subject. There is no predictive value in looking at the correlation of biomarker levels with weight loss.
Keeping weight lost stable also presents a major challenge to the patient. It is known that only one year after a weight loss intervention, about one-third of the lost weight is regained (Hensrud, Obes. Res. 9 Suppl 4, 348S-353S, 2001). Moreover, diet-induced weight loss induces several physiological changes that facilitate weight regain (Sumithran and Proietto, Clin. Sci. Lond. Engl. 1979 124, 231-241 (2013)). These changes include alterations in energy expenditure, substrate metabolism and hormone pathways involved in appetite regulation. Our understanding of these physiological and molecular changes remains so far limited.
The solution for successful planning and design of dietary interventions, for example low calorie diets, lies in the availability of a method which predicts a weight loss trajectory. In addition, successful planning and design of weight management interventions would be aided by the availability of a test to predict the success (or failure) of a patient at keeping his/her weight loss stable during a weight maintenance program.
United States Patent Application US 2011/0124121 discloses a method for predicting weight loss success. The methods disclosed comprises selecting a patient who is undergoing or considering undergoing a weight loss therapy such as gastric banding, measuring one or more hormone responses of the patient to caloric intake and predicting success of a weight loss therapy based on the hormone response. The hormones measured are gastrointestinal hormones such as a pancreatic hormone.
European Patent Application EP 2 420 843 discloses a method for determining the probability that a person will maintain weight loss after an intentional weight loss by determining the level of angiotensin I converting enzyme (ACE) before and after the dietary period.
There is, however, still a need for a method of accurately predicting the degree of weight loss and weight maintenance in a subject. Consequently, it was the objective of the present invention to provide biomarkers that can be detected easily and that can facilitate the prediction of weight loss and weight maintenance in a subject. Such biomarkers may be used to predict weight trajectories during weight loss and during weight maintenance and may help for stratification of patients into adapted treatment groups according to their biological weight loss and weight maintenance capacities.
Protocadherin Fat 4, also known as cadherin family member 14 (CDHF14) or FAT tumor suppressor homolog 4 (FAT4), is a protein that in humans is encoded by the FAT4 gene. FAT4 is associated with the Hippo signaling pathway. The Hippo pathway has emerged as a conserved signaling pathway that is essential for the proper regulation of organ growth in Drosophila and vertebrates (Halder, 2011, Development, January; 138(1):9-22).
It has recently been shown that Drosophila Fat (Ft) cadherin has a direct role in regulating mitochondrial morphology and metabolism (Sing et al., 2014, Cell, 158, 1293-1308). It was shown that proteolytic cleavage of Ft releases a soluble fragment (Ftmito) that is imported into the mitochondria and that such cleavage functions as a switch mechanism to coordinate cell cycle and metabolism. It was suggested that altering the levels of Ftmito may allow an organism to directly adjust metabolic rates in accordance with changing energy requirements.